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Matrices based on HMPC, sodium carboxymethylcellulose & ethylcellulose
Relating to Invited Lecture j--Material
Cellulose ethers, especially hydroxypropylmethylcellulose (HPMC) or sodium carboxymethylcellulose (N&MC), are used in oral controlledrelease matricer. Ethylcellulose, a hydrophobic polymer that cmot swell in a maoner similar to HPMC or N&MC, was considend in admixture with HPMC or NaCMC, for their potential to modify the release rate of propranolol hydrochloride. sodium K4M, 2208 (Methocel Hydmpropylmethylcellulose carboxymethylcellulosc (Blanose 7H4XF). ethylcellulose 7 cP (Ethocel STD7 PREM), propmnolol hydrochloride B.P. (cl25 pm) and magnesium steamte (B.D.H.) were used. Tablets were directly compressed at 182 MNm-2. They contained 160 mg propranolol hydrochloride, 285 mg either HPMC:ethylcellulose or NaCMC:ethylcellulosc at the ratios O:I, 1:3, l:I, 3:l or 1:0 and 0.75% w/w magnesium stearate. Dissolution was determined as previously described [l]. Data corresponding to 5 to 60% release, were fitted to equation 1. Equation I Q = K,(t-1)” Q is the percentage of drug released at time t, K, is a dissolution rate constant, I is a lag time and n is the release exponent for tablets containing HPMC EC. Root time release rates were also determined. As the proportion of EC increased in matrices containing HPMC the release rates inceased from 2.7 f 0.2% min-” (HPMC) to 4.8 f 0.1% min-‘A(EC), n did not change, being in the range 0.50 - 0.61, indicative of diffusion being the main release mechanism. As the EC portion in matrices containing NaCMC increased, the release rates increased from 3.5 f 0.1% min-‘h (NaCMC) to 7.2 f 0.2% min-” for matrices containing I :3 NaMCM:EC. Higher values of n (0.86 - 1.45) indicated a high swelling nature and erosion in these matrices. [l) Dabbagh, M.A., Ford, J.L. et al J. Pharm Phannacol., 45 (1993) 1134.
The use of polymers, which enhance the viscosity of the vehicle or gel1 in situ after instillation were proposed to prolong the residence of eyedrops in the precomeal area and consequently to improve the bioavaitability of ophthalmic drugs. In the present study the rheological behaviour and mucoadhesive properties of various carmgeenans were studied and compare to gellan gum (Gelrtte). which is used in commercial eyedrops, in order to evaluate their use as ophthalmic viscolysers. The iota, kappa and the mixture of carrageenans (Aubygel X52) exhibited vfscoetastic properties and gelling. which depends on the composition of the vehicle. The various carrageenans tested did not possess mucoadhesive properties. In general, the properties Of iota and kappa and the mixture of carrageenans resemble the characteristics of gellan gum. As carrageenans are well tolerated, they could be promising adjuvants for the development of viscous eyedrops.
Science (P3.031-P3.089)
s175
Due to the relatively poor biocompatibility of the existing in~ccular lenses (IOLs) used in catarzt nplacemcnt surgery thcrc is a pressing riced to develop new materials which will address the key problems of pmtcin adsorption, lens ccl1 overgrowth and bacterial attachment within the eye. Accordingly we have pursued a comprehensive program of material synthesis based upon the application of phosphorylcholine (PC) technology to a poly(mcthyhncthacrylatc) (EMMA) base mat&I. In panicular wc have concenhatcd on the dcvclopmcnt of a scrics of PC incorporating materials which can bc cross linked by moderate heat treatment (CPCs). These materials were then subjected to a phased series of scmcns. Phase I screens wcm designed to remove candidate materials which failed to show general reductions, relative to PMMA, in 313 fibroblast attachment, fibrinogen adsorption and S.epidermidis adhesion. Materials passing phase 1 tests were subjected to mom dctaiIcd phase II screens designed to address key challenges within the ocular cnvimnmcnt. These phase II screens included the assessment of lens cell adhesion, cell pmlifcration, and macrophage attachment. All results are expressed in percentage of unmodiicd contml values. Phase I A= _nlrol va& Fibrinogen Adsorption 32f17 3T3 tibmblast adhesion 7+3 Bacterial Adhesion lof6 Phase II Asw &Gs?ntaee of Control value Fibmblast proliferation 0.68 Macmphage Adhesion 14*4 Rabbit Lms Cell Adhesion lM12 These data show that the CPC coatings signiticantly enhanced the biocompatibility of the PMMA base mat&d in all the criteria assayed.
Hyaluronan (HA) IS a high molecular werght polysaccharlde prevalently dispersed within the extracellular matrix of mammalian connective tissue such as the skin. with many physical and biological functlons. HA formulations are currently being developed for a number of medicinal. surgical and pharmaceutical drug targeting applications. The arm of this study was to evaluate, compare and character& various HA samples by examining the rheological properties of their gels with a nondestructive dynamic rheobical test using the Cani-bled CSL UK rhecmeter. The viscosity-average molecular weight of HA samples was also calculated by use of U-tube capillary (grade A) Viscometry. Experiments were carried out using hyaluronan extracted from rooster comb [RC] (MWt 1.3 x 106), human umbilical cord [NC] (UWt 3-5 x 106) and three sources supplied by Hyal Pharrnaceubcal Corporation originating from cocks comb of MWts 600,000, 676,000 and 751.000. Each sample was loaded between a 4 cm parallel plate and subjected to a frequency sweep function up to a frequency of I-20 Hz at a fixed stress of 5 Pa at 25”C, and the rheological parameters G’, the storage modulus and G”, the loss modulus determined. Capillary vlscometry provided intrinsic viscosities for dilute HA solutions and corresponding molecular weights were calculated using the Mark-Houwink equation. For each source of hyaluronan. G’and G” was found to be a function of HA concentration. At 2.5% w/w, G’and G”was dependent not only upon the molecular weight but also on the source of HA, due possibly to tts method of Isolation and/or associated protein content For RC and HUC, G’ was always greater than G” over the l-20 Hz frequency range, tndlcating the predominant elastic nature of these particular sources of HA. Further tests showed that the rheological properties of the gel varied as a functton of pH and temperature; lowering pH increased G’, while higher temperatures decreased gel stability thus reducing G’. In conclusion. the use of the dynamic technique provides a suitable rheological method for evaluating as well as charactensing the structural properties of HA gels, and while providing regulatory authorities with valuable information, it can also be used in the development of novel hyaluronan formulations for targeted drug delivery
Cellulose ethers, especially hydroxypropylmethylcellulose (HPMC) or sodium carboxymethylcellulose (N&MC), are used in oral controlledrelease matricer. Ethylcellulose, a hydrophobic polymer that cmot swell in a maoner similar to HPMC or N&MC, was considend in admixture with HPMC or NaCMC, for their potential to modify the release rate of propranolol hydrochloride. sodium K4M, 2208 (Methocel Hydmpropylmethylcellulose carboxymethylcellulosc (Blanose 7H4XF). ethylcellulose 7 cP (Ethocel STD7 PREM), propmnolol hydrochloride B.P. (cl25 pm) and magnesium steamte (B.D.H.) were used. Tablets were directly compressed at 182 MNm-2. They contained 160 mg propranolol hydrochloride, 285 mg either HPMC:ethylcellulose or NaCMC:ethylcellulosc at the ratios O:I, 1:3, l:I, 3:l or 1:0 and 0.75% w/w magnesium stearate. Dissolution was determined as previously described [l]. Data corresponding to 5 to 60% release, were fitted to equation 1. Equation I Q = K,(t-1)” Q is the percentage of drug released at time t, K, is a dissolution rate constant, I is a lag time and n is the release exponent for tablets containing HPMC EC. Root time release rates were also determined. As the proportion of EC increased in matrices containing HPMC the release rates inceased from 2.7 f 0.2% min-” (HPMC) to 4.8 f 0.1% min-‘A(EC), n did not change, being in the range 0.50 - 0.61, indicative of diffusion being the main release mechanism. As the EC portion in matrices containing NaCMC increased, the release rates increased from 3.5 f 0.1% min-‘h (NaCMC) to 7.2 f 0.2% min-” for matrices containing I :3 NaMCM:EC. Higher values of n (0.86 - 1.45) indicated a high swelling nature and erosion in these matrices. [l) Dabbagh, M.A., Ford, J.L. et al J. Pharm Phannacol., 45 (1993) 1134.
The use of polymers, which enhance the viscosity of the vehicle or gel1 in situ after instillation were proposed to prolong the residence of eyedrops in the precomeal area and consequently to improve the bioavaitability of ophthalmic drugs. In the present study the rheological behaviour and mucoadhesive properties of various carmgeenans were studied and compare to gellan gum (Gelrtte). which is used in commercial eyedrops, in order to evaluate their use as ophthalmic viscolysers. The iota, kappa and the mixture of carrageenans (Aubygel X52) exhibited vfscoetastic properties and gelling. which depends on the composition of the vehicle. The various carrageenans tested did not possess mucoadhesive properties. In general, the properties Of iota and kappa and the mixture of carrageenans resemble the characteristics of gellan gum. As carrageenans are well tolerated, they could be promising adjuvants for the development of viscous eyedrops.
Science (P3.031-P3.089)
s175
Due to the relatively poor biocompatibility of the existing in~ccular lenses (IOLs) used in catarzt nplacemcnt surgery thcrc is a pressing riced to develop new materials which will address the key problems of pmtcin adsorption, lens ccl1 overgrowth and bacterial attachment within the eye. Accordingly we have pursued a comprehensive program of material synthesis based upon the application of phosphorylcholine (PC) technology to a poly(mcthyhncthacrylatc) (EMMA) base mat&I. In panicular wc have concenhatcd on the dcvclopmcnt of a scrics of PC incorporating materials which can bc cross linked by moderate heat treatment (CPCs). These materials were then subjected to a phased series of scmcns. Phase I screens wcm designed to remove candidate materials which failed to show general reductions, relative to PMMA, in 313 fibroblast attachment, fibrinogen adsorption and S.epidermidis adhesion. Materials passing phase 1 tests were subjected to mom dctaiIcd phase II screens designed to address key challenges within the ocular cnvimnmcnt. These phase II screens included the assessment of lens cell adhesion, cell pmlifcration, and macrophage attachment. All results are expressed in percentage of unmodiicd contml values. Phase I A= _nlrol va& Fibrinogen Adsorption 32f17 3T3 tibmblast adhesion 7+3 Bacterial Adhesion lof6 Phase II Asw &Gs?ntaee of Control value Fibmblast proliferation 0.68 Macmphage Adhesion 14*4 Rabbit Lms Cell Adhesion lM12 These data show that the CPC coatings signiticantly enhanced the biocompatibility of the PMMA base mat&d in all the criteria assayed.
Hyaluronan (HA) IS a high molecular werght polysaccharlde prevalently dispersed within the extracellular matrix of mammalian connective tissue such as the skin. with many physical and biological functlons. HA formulations are currently being developed for a number of medicinal. surgical and pharmaceutical drug targeting applications. The arm of this study was to evaluate, compare and character& various HA samples by examining the rheological properties of their gels with a nondestructive dynamic rheobical test using the Cani-bled CSL UK rhecmeter. The viscosity-average molecular weight of HA samples was also calculated by use of U-tube capillary (grade A) Viscometry. Experiments were carried out using hyaluronan extracted from rooster comb [RC] (MWt 1.3 x 106), human umbilical cord [NC] (UWt 3-5 x 106) and three sources supplied by Hyal Pharrnaceubcal Corporation originating from cocks comb of MWts 600,000, 676,000 and 751.000. Each sample was loaded between a 4 cm parallel plate and subjected to a frequency sweep function up to a frequency of I-20 Hz at a fixed stress of 5 Pa at 25”C, and the rheological parameters G’, the storage modulus and G”, the loss modulus determined. Capillary vlscometry provided intrinsic viscosities for dilute HA solutions and corresponding molecular weights were calculated using the Mark-Houwink equation. For each source of hyaluronan. G’and G” was found to be a function of HA concentration. At 2.5% w/w, G’and G”was dependent not only upon the molecular weight but also on the source of HA, due possibly to tts method of Isolation and/or associated protein content For RC and HUC, G’ was always greater than G” over the l-20 Hz frequency range, tndlcating the predominant elastic nature of these particular sources of HA. Further tests showed that the rheological properties of the gel varied as a functton of pH and temperature; lowering pH increased G’, while higher temperatures decreased gel stability thus reducing G’. In conclusion. the use of the dynamic technique provides a suitable rheological method for evaluating as well as charactensing the structural properties of HA gels, and while providing regulatory authorities with valuable information, it can also be used in the development of novel hyaluronan formulations for targeted drug delivery